Abstract:

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a
nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

日本語要旨:

全エキソーム解析でネマリンミオパチー(NM)の原因遺伝子MYPNを同定した。NMは近位筋優位の筋力低下、筋緊張低下、呼吸筋低下を呈する先天性ミオパチーで、心筋合併症は稀である。原因遺伝子は10種類報告されているが、約25-30％の症例では遺伝学的原因は不明である。重症度は様々で、重症な症例の多い核内棒状封入体をもつサブタイプでは原因遺伝子としてACTA1遺伝子のみが報告されている。 病理学的にはNMと診断されているものの遺伝学的原因が不明な症例に全エキソーム解析を行ったところ、4家系4症例にMYPM遺伝子劣性変異を認めた。いずれの症例も小児期から成人期の発症で、比較的軽症かつ緩徐進行性の経過であり、40歳代で歩行障害を認めた。内2症例に呼吸筋障害、心筋障害、病理学的に核内棒状封入体を認めた。MYPM遺伝子が作るタンパク質は筋サルコメアの構成成分でありZ線に位置するが、患者群ではこのタンパク質がほとんど消失していた。MYPM遺伝子のナンセンス変異をもつノックインマウスでは、Z線の構造異常やネマリン小体様の凝集物が電子顕微鏡下で確認され、NMの病態が再現できた。 本研究により、比較的軽症のNM症例、特に心筋障害を合併もしくは核内ロッドを認める症例では、MYPM遺伝子のスクリーニングの検討が必要と示唆された。